Defensive Protein Linked to Asthma

WEDNESDAY Nov. 14, 2007 -- A protein that may have originally evolved to help protect the airways now appears to be a biomarker that indicates severe asthma. And it may also play a role in the development of asthma, according to new research.

Reporting in the Nov. 15 issue of the New England Journal of Medicine, Yale University researchers said that people with severe asthma were more likely to have elevated levels of the protein known as YKL-40 in their blood compared to people without asthma.

"We believe that it's a marker of the inflammatory response associated with asthma," said the study's lead author, Dr. Geoffrey Chupp, an associate professor of medicine at Yale University School of Medicine. And, he added, "These new novel family of molecules could be very important in asthma pathogenesis. Down the road, there could be new treatments and new ways to characterize asthma."

YKL-40 is what's known as a chitinase-like protein. It attaches itself to chitin, an abundant substance found in fungi, crustaceans and in insects like dust mites and cockroaches. It's also present in the pharynx and eggs of parasitic worms called helminths. Infection with helminths used to be common but is now rare in developed countries, according to the author of an accompanying editorial in the same issue of the journal, Dr. Burton Dickey, chairman of pulmonary medicine at M.D. Anderson Cancer Center in Houston. These worms migrate through the skin into the bloodstream and travel through the lungs to get into the gastrointestinal tract, he said.

Humans don't manufacture chitin but do produce chitinases (enzymes that break down chitin) and chitinase-like enzymes (enzymes that bind to chitin, but don't break it down). The presence of chitin in the lungs may make the body believe that it has a helminth infection that it needs to defend against, Dickey said. Unfortunately, he pointed out, this defense mechanism may now be reacting to harmless dust mites instead.

However, both Dickey and Chupp noted that the new study doesn't prove that YKL-40 is a cause of asthma, only that elevated levels appear to be a marker of severe asthma.

Chupp and his colleagues at Yale, the University of Paris and the University of Wisconsin recruited 253 adults -- some with asthma and some without. Levels of YKL-40 were measured from blood samples at all three study sites. In Paris, the researchers also conducted lung biopsies.

The researchers found that, overall, people with asthma had higher levels of YKL-40 in both blood levels and in lung biopsies than did people without the airway disease. In the Yale group, the average levels of YKL-40 were 49.1 nanograms (ng) per milliliter of blood for people with mild asthma, 58.3 ng per milliliter for controls, 68.4 for those with moderate asthma, and 77 ng per milliliter for those with severe asthma. The findings were similar in both the Paris and the Wisconsin groups, the researchers said.

Chupp pointed out that the one of the biggest potential benefits of the new research is that YKL-40 is easily detected in the blood.

The study's senior author, Dr. Jack Elias, chairman of medicine and a professor of immunobiology at Yale, said in a prepared statement: "This may allow us to identify a subpopulation of patients with severe asthma and give us insights into the biologic processes that make the disease so severe in these individuals.

"Our studies also have demonstrated that eliminating YKL-40 decreases specific types of tissue inflammation, which could be of particular benefit to asthmatic patients with an elevated level of this protein," he added.

Dickey said: "It's always been something of a mystery why asthma prevalence has risen in the 20th century, and this may help us begin to understand it. Chitinase and chitinase-like proteins are a highly effective protective response against worms, and for most of human history, we have been burdened with these parasites. An asthma-like response probably evolved to protect against worms. Now it appears this protective response may have gone awry and something as harmless as dust mites or pollen is initiating it."

Dickey said if chitin truly is triggering an inflammatory airway response that leads to asthma, these findings could open up whole new avenues of research and new therapies.

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